As used in the medical field, a bone cement generally refers to a biocompatible material that can be used to repair damaged or diseased bone or other hard tissues. Specifically, bone cement is used to fill voids or gaps in bones, to affix or anchor an orthopedic implant in a prepared area of the body, or to repair or replace damaged or diseased teeth. Ideally, the bone cement closely assimilates the mechanical characteristics of the hard tissue that the cement is intended to repair or replace.
In most applications, bone cement is made from an acrylic polymeric material. Typically, the bone cement is comprised of two components: a dry or powder component and a liquid component, which are subsequently mixed together to form a resulting cured cement. The dry component of a bone cement system generally includes an acrylic polymer, such as polymethyl methacrylate (PMMA). The PMMA is typically present in the form of small polymer beads, but can also appear in the form of amorphous particles. Regardless, the PMMA powder generally has the consistence of flour. In addition to the acrylic polymer, a polymerization initiator, such as benzoyl peroxide, can also be added to the powder component for the purpose of later initiating the free-radical polymerization process. The polymerization initiator can be added as small particles or can be incorporated into the beads made from the polymer. The liquid component, on the other hand, typically contains a liquid monomer that is mixed with the corresponding acrylic polymeric powder. One example of a liquid monomer is methyl methacrylate (MMA). The liquid component can also contain an accelerator, such as an amine (e.g., N,N-dimethyl-p-toluidine). A stabilizer, such as hydroquinone, can also be added to the liquid component to prevent premature polymerization of the liquid monomer. When the liquid component is mixed with the powder or dry component, initially, the liquid monomer wets the polymeric powder. Since the powder (PMMA) is soluble in the liquid monomer, the solid polymer beads partially begin to dissolve or swell in the liquid monomer. The polymerization reaction starts as soon as the two components are mixed. The amine accelerator reacts with the initiator to form free radicals which begin to link monomer units to form polymer chains intermixed with the dissolved portion of the polymer powder. In the next two to four minutes, the polymerization process proceeds, changing the viscosity of the mixture from a syrup-like consistency (low viscosity) into a dough-like consistence (high viscosity). In this state, the bone cement is applied to a prepared area of the body where it is to be used. Ultimately, further polymerization and curing occur until the cement is fully hardened. Typically, it takes anywhere from about 5 minutes to about 20 minutes for the bone cement to fully cure after the two components are mixed. Since the polymer beads only partially dissolve during mixing, the resulting solid includes a dispersion of polymeric beads contained in a matrix of the acrylic polymer.
Although bone cement is widely utilized in a variety of orthopedic and dental applications, its glassy, amorphous nature as a thermoplastic material is responsible for its relatively low strength if used in load-bearing applications. This, and the high glass transition temperature (Tg) of PMMA are associated with its poor fatigue performance. The presence of the porosity and other stress concentration sites introduced during application contributes further to the weakness of PMMA bone cement. In fact, fatigue fracturing has been found to be one of the main causes for the loosening and cement fragmentation during the long-term use of the traditional PMMA bone cement. Although a few techniques have been used to address the shortcomings associated with the PMMA, long-term cement fatigue is yet to be circumvented.
To improve the mechanical properties of PMMA bone cement, in general, certain aspects of the composite technology have been explored. For example, fibers made of carbon, steel, KEVLAR, ultrahigh molecular weight polyethylene (UHMW-PE) and titanium have been incorporated into the PMMA matrix as reinforcing fillers to improve its mechanical properties. Although these composites did show some improvement in mechanical properties, such as fracture toughness and fatigue resistance, the incompatibility between fibers and matrix posted possible weak interfacial bonding. To overcome the problems with the traditional composites, a new composite technology was developed which uses PMMA fibers as a fillers to produce the self-reinforced PMMA composites. While commercial PMMA in bulk form has a strength of about 50 MPa and a breaking elongation of about 5%, PMMA fibers having a strength of 220 MPa, modulus of 8 GPa, and a breaking elongation of 25% were successfully prepared by melt extrusion and drawing (Buckley, C. A., Gilbert, J. L. and Lautenschlager, E. P., Thermomechanical processing of PMMA into high strength fibers, J. Appl. Polym. Sci., 44, 1321, 1992). Such fibers are highly oriented. Because of the increased elongation at break, the PMMA fibers resulted in a significant improvement in ductility of the self-reinforced composite compared to single-component polymer. Using PMMA fibers, Gilbert et al prepared self-reinforced PMMA composites with a 60% fiber fraction and tested their mechanical properties (Gilbert, J. L., Ney, D. S. and Lautenschlager, E. P., Self-reinforced composite poly(methyl methacrylate): static and fatigue properties, Biomaterials, 16, 1043, 1995). The results indicated that although the modulus of composites showed a limited increase in comparison to pure PMMA, the ultimate elongation increased significantly, suggesting high toughness for the self-reinforced PMMA composites. The single edge notched tests showed an increase of almost 100% in fracture toughness for composites. The study of failure mechanisms revealed that the composites absorbed much energy before fracture. Fatigue experimental results showed that the composites had significant fatigue strength improvement over that of bulk PMMA. It was claimed that the fiber-matrix bond in self-reinforced PMMA composites is uniform and continuous through the composite.
Perhaps the most common application for bone cement is in the fixation of prosthetic devices. Prosthetic devices are artificial materials used to replace or strengthen a particular part of the body. When implanting a prosthesis, first a receiving site or cavity is prepared in an adjoining bone. In particular, the bone can be cut and reamed out in order to accommodate the prosthesis. A bone cement is then mixed and placed in the receiving site or cavity. A prosthesis is positioned in the bone cement and the bone cement is hardened affixing the prosthesis to the bone.
The above process for implanting a prosthetic device is generally accepted within the art and has proven to be a successful one for repairing or replacing damaged bones and the like. Prosthetic devices, however, can be prone to loosening within the bone cavity over time. In particular, the acrylic bone cement has been universally considered the weakest link in the implant design. Most bone cements are neither as strong nor as flexible as bone tissues. Consequently, the bone cement can break away from the prosthesis, can fracture, or can develop fatigue cracks when exposed to repeated loads. Because problems can develop in the bone cement mantle or bed surrounding a prosthesis, it is important that the condition of the implant be monitored after surgery. However, bone cement, like most polymers, is relatively radiolucent, meaning that the bone cement is transparent to X-rays. Consequently, in order to inspect the bone cement mantle post-operatively, radiopacifiers are commonly added to the dry component of a bone cement system in a sufficient amount to give the resulting bone cement the necessary radiopacity for examination by X-rays. Unfortunately, radiopacifiers, such as barium salts and certain metal oxides, when added to bone cement, tend to reduce the mechanical properties of the cement. Radiopacifiers, which have a higher density and polarity than the polymeric material they are mixed with, tend to collect together and clump or agglomerate in the bone cement. These agglomerates have been shown to act as stress concentration sites and have been shown to decrease the ultimate flexural strength, intrinsic tensile strength, fatigue strength, as well as the fracture toughness of the cement. Due to these deficiencies, many of those skilled in the art have attempted to improve the mechanical properties of radiopaque bone cements. For instance, in U.S. Pat. No. 4,500,658 to Fox, a radiopaque acrylic resin is disclosed. Specifically, a radiopaque inorganic pigment is distributed in the polymer beads that are incorporated into the bone cement. The polymer beads incorporating the pigment are formed by suspension polymerization. U.S. Pat. No. 4,791,150 to Braden, et al. also teaches incorporating particles of an opacifier into the polymer beads. By incorporating the opacifier particles into polymer beads, the particles will remain trapped within the beads during formation of the bone cement, preventing the particles from forming agglomerates in the polymer matrix. U.S. Pat. No. 5,975,922 to Damian, et al. teaches the use of a radiopacifier that is microencapsulated with a bone cement compatible material. When combined with the liquid monomer, the bone cement compatible material dissolves releasing the radiopacified particles into a bone cement matrix. By being microencapsulated, the radiopacifier is prevented from agglomerating in the cement. Instead, the radiopacifier particles become dispersed through the bone cement matrix, which not only creates a radiopaque cement, but also increases the fatigue life of the cement. Other bone cement materials containing radiopacifiers are disclosed in U.S. Pat. No. 4,547,390 (Ashman, et al.); U.S. Pat. No. 4,535,485 (Ashman, et al.); U.S. Pat. No. 4,456,711 (Pietsch, et al.); U.S. Pat. No. 4,404,327 (Cruganola); and U.S. Pat. No. 3,715,331 (Molnar). Although U.S. Pat. No. 5,795,922 provides a scientifically viable solution to the problem of clustering or agglomerating radiopacifier particles, the use of the complex and costly microencapsulation technology to pre-encase the radiopacifier particles to prevent clustering is technologically impractical and economically forbidding. This provided an incentive to explore novel approaches to prevent the radiopacifier from aggregation or clustering using technologically and economically feasible methods as provided by the present invention.
Different types of antibiotic-loaded PMMA bone cements are used extensively for treatment and prophylaxis of bone infection. In most cases, manufacturers make their own antibiotic bone cements by simply mixing solid antibiotic particles with the PMMA powder component of plain bone cement (K-D. Kühn, Bone Cements, Springer, N.Y., 2000, p. 149.). Most commonly incorporated antibiotics, such as gentamicin, tobramycin, are used as water soluble salts, which makes them physically incompatible with the hydrophobic component of the PMMA plain cement. This and the fact that they are mixed with the solid PMMA powder results in their presence as agglomerates in the cured cement. This results in having unevenly distributed, relatively large antibiotic aggregates, which (1) compromise the mechanical properties of the cement; (2) interfere with timely and prolonged release of the drug at predictable rates; and (3) require an increase of the initial concentration of the drug for attaining early clinical efficacy. These limitations created a need to explore a new approach to incorporate antibiotics in the bone cement to circumvent the noted limitations. And this invention deals with a new method for producing bone cements with evenly distributed antibiotic agents in a molecular form or as micro-/nanoparticles.